Regulation of food intake and energy expenditure is crucial in maintaining a stable body weight. Excessive energy intake leads to obesity, which is a leading risk factor in many diseases including diabetes and hypertensin. Neuropeptides in the hypothalamus play a critical role in regulating energy balance. A detailed knowledge of hypothalamic peptides and their receptors in controlling feeding, satiety and energy expenditure is key in understanding the causes of obesity and related disorders. Urocortin 3 (Ucn 3) is a new neuropeptide identified in rodents and humans with strong central appetite suppressive effect. Ucn 3 expressing neurons heavily innervate the ventromedial hypothalamus (VMH). Ucn 3 neurons that innervates the VMH are stimulated by stress and anoretic hormone, leptin. The receptor for Ucn 3, the type 2 CRF receptor (CRFR2), is highly expressed in the VMH and its expression is regulated by the energy status of the animals. Direct injection of Ucn 3 into the VMH suppresses food intake, elevates blood glucose levels and activates anorectic POMC neurons in the arcuate nucleus of the hypothalamus. The VMH has been recognized as a satiety center and for its ability to sense blood glucose levels, yet the mechanism by which this brain area regulates feeding and blood glucose is unknown. Thus, we hypothesize that Ucn 3 and its receptor is a critical molecular mediator in the VMH to regulate energy homeostasis. The major objectives of this project are to (1) identify the neurocircuits that mediate the effect of Ucn 3 in the VMH, (2) determine neuropahtwys by which stress and/or leptin activate Ucn 3 neurons that project to the VMH and (3) ascertain the physiological role of endogenous Ucn 3 and CRFR2 in the VMH in regulating feeding under basal and stress conditions.The project will first utilize a number of functional neuroanatomical approaches to elucidate the efferent projections of Ucn 3- responsive neurons (CRFR2 positive) and the neuropathways that mediate the stimulatory effect of stress and/or leptin on Ucn 3 neurons that project into the VMH. Finally Ucn 3 null mice and a small interference RNA approach to knockdown CRFR2 expression in the VMH will be used to examine the physiological role of Ucn 3 and its receptor in the VMH in regulating food intake and energy homeostasis. The proposed project will provide a significant insight into mechanisms through which Ucn 3 in the VMH regulates feeding and controls energy homeostasis. PUBLIC HEALTH RELEVANCE: Obesity has reached epidemic proportions in the US. Thus, there is a pressing need to identify the cause of obesity. Ucn 3 peptide and its receptor are a previously underappreciated peptide system in regulating sateity. A thorough study of the brain Ucn 3 in feeding and energy homeostasis will increase our understanding of the causes of obesity, improve differential diagnosis of obesity syndromes, and ultimately identify potential new targets for drug development to treat the disease and metabolic related disorders.